Although lung cancer is often considered primarily an environmentally induced disease, increasing evidence supports the hypothesis that lung cancer is in part determined by genetic factors. The main goal of this project is to ultimately discover genetic markers that identify those persons at highest risk for developing lung cancer after accounting for smoking exposure. The translational application of these findings will be used to find markers used to identify high-risk individuals who would be most suitable for chemoprevention studies. The Specific Aims of this project involve furthering the understanding of specific factors which may increase the risk of lung cancer or genetic markers which may be signs of a genetic susceptibility. We will continue to accrue newly diagnosed lung cancer patients of diverse ethnic backgrounds for the study of possible biomarkers of lung cancer risk. Susceptibility to two specific chemical carcinogens have been studied as part of the SPORE vis a vis susceptibility to lung cancer. First, we have studied and will continue to study bleomycin induced chromosomal breakage of lymphocyte DNA in lung cancer patients. We will further study the association of bleomycin induced chromosomal breaks and familial aggregation of lung cancer. In addition we will study ethnic differences in susceptibility to bleomycin induced chromosomal breaks in Caucasians and African Americans. Secondly, we will study benzo [a] pyrene diol epoxide (BPDE) induced loss of genetic materials on chromosome 3p which we have observed at increased frequency in lung cancer patients compared to controls such that a person with increased BPDE induced breaks has a 14-fold increased risk of developing lung cancer. It is not clear, however, whether loss at 3p is important because of the loss of a critical gene or genes on 3p or whether or not the loss merely reflects a very high degree of chromosome fragility at sites on 3p. In this study we will compare the rate of BPDE induced chromosome 3p loss at 3p2l.3 vs. 3pl4.2, a known fragile site. A new Aim of our Project will involve the study of subjects with dysplasia, a histologic precursor lesion associated with increased risk of lung cancer, and genetic polymorphisms of the Phase I and Phase II metabolic enzymes. It is anticipated that the additional genetic studies of individuals with dysplasia will lead to a more complete understanding of the genetic pathways in lung cancer development.